Because of advances in highly active antiretroviral therapy (HAART), the incidence of oral and esophageal candidiasis and other opportunistic infections is currently reduced in HIV+ individuals compared to previous years. Unfortunately the reduced incidence is not correlated with major advances in preventive or treatment methodologies for candidiasis, but rather with the ability to suppress HIV infection and restore adequate anti-fungal immunity by lifelong administration of HAART. The uncertainties that accompany the long-term success of HAART, the inability of some individuals to tolerate or accept the therapy, and the lack of availability of HAART therapy to the majority of the global population point to the need for a basic understanding of the pathogenesis of oral and esophageal candidiasis that can be applied to prevention in those at risk and therapy in infected HIV+ individuals. The recognition of Hwpl as an adhesin and virulence factor and the involvement of mammalian transglutaminases in adhesion have posed important new questions and have opened new avenues of exploration that will benefit our understanding of the pathogenic mechanisms of candidiasis. New aims are proposed that explore mammalian parameters that lead to stabilized adhesion. These include characterizing adherent buccal epithelial cells (BECs) and identifying BEC proteins that become cross-linked to rHwpl. With the availability of new technologies including bioinformatics, cell biology and microarray analyses that build upon molecular genetic and biochemical tools recently acquired, we currently have unprecedented opportunities to decipher the complexities of candidiasis and develop non-toxic therapeutic interventions.